Various pharmaceuticals, such as CNS active agents cause severe side-effects that generally worsen with increasing doses. Some classes of CNS active agents that require increasing doses include pain reducing drugs, selective serotonin re-uptake inhibitors, antidepressants, anti-convulsants, hypnotics, anesthetics, sedative agents, angiolytics, NSAIDs, xanthines, antipsychotics, appetite suppressants, sleep agents, antibiotics, antivirals, insulin resistance drugs, antihypertensives, and anti-asthma drugs. At high doses, many CNS active agents rapidly lose their effectiveness, induce pharmacologic tolerance, and cause increasingly severe side-effects. Lowering the dose of the CNS active agent, however, does not address the problem because reducing the dose to prior levels results in significantly lower therapeutic efficacy.
Combinations of centrally active agents have been used in an effort to overcome the current disadvantages of single agent use. In local anesthetic formulations, locally acting adrenergic agonists, such as epinephrine, are known to enhance the local activity of analgesic drugs and improve therapeutic efficacy. For example, it has been demonstrated that a higher dosage of epinephrine potentiated the effects of local anesthesia. (Morganroth et al. 2009). Furthermore, several selective β2 agonist drugs have been used in anesthesia, either alone or in combination, with various opiate or inhalational anesthetics, and have been found to reduce the dose requirement for opiates, halothane, or ketamine (Verstegen 1989; Nevalainen et al. 1989; Moens and Fargetton 1990). Additionally, U.S. Pat. No. 5,605,911 discloses the use of an β2 agonist to block the neurotoxic effects, such as hallucinations and neuronal damage, of an NMDA antagonist. Similarly, U.S. Pat. No. 6,562,855 teaches that co-administration of an NMDA receptor antagonist and an β2 adrenergic agonist both potentiates the effects of anesthesia and diminishes the side effects compared to administration of anesthesia alone.
U.S. Pat. No. 6,833,377 teaches that the activity of systemically administered CNS drugs may be significantly potentiated by the co-administration of a compound which affects peripheral chemoreceptors (i.e. pseudoephedrine (PSE)) and a stimulator of osmoreceptors (osmoactive polymers or sorbitol). This potentiation results in a reduction of the minimal effective dose of a variety of CNS active agents, which in turn reduces the associated side effects.
Such combinations, however, are not without their problems. Thus, there still exists a need for novel combinations of CNS active agents and neuromodulators to potentiate the pharmacological effect of the CNS active agent, reduce dose-dependent side-effects, avoid tolerance/tachyphylaxis problems, and overcome the resistance and noncompliance issues.
More specifically, there is a clinical need to develop “non-sedating” GABA agonists for therapeutic activities where sedation-related side effect damages the quality of life and cognitive functioning of the patient, causing the patient to live most of the day in a daze and making it dangerous to drive vehicles and operate machinery. However, attempts to develop these “non-sedative” benzodiazepines have failed as the prior art teaches that sedation effects of benzodiazepine treatment are linked to the GABA-inhibiting therapeutic activity. In addition, attempts have been made to develop non-sedating anxiolytic drugs by chemical modification of the active agent, but no benzodiazepine receptor partial agonist has emerged as a viable alternative.
The optimal anxiolytic drug product will be capable of producing a robust anxiolytic action by having a more rapid onset of action than current therapies while potentially reducing the number of side effects. This drug would be comparable to benzodiazepines, but lacking their limiting side effects at therapeutic doses. This new drug would represent an important advancement in the treatment of anxiety disorders. Even if it is possible that a new, chemically-modified non-sedative GABA agonist may be finally developed, there is an advantage in the utilization of a drug product combination from known, approved, and available pharmaceutical ingredients. Such an approach reduces the risk of potential unknown toxicity, and the long term development investment required of new pharmaceutical ingredients.
In light of the prior art, the inventors surprisingly discovered that (1) the reduction of sedation-associated side effects of CNS active agents is possible using the conventional dosage of the CNS drug; (2) chemoreceptor stimulators (i.e. pseudoephedrine (PSE) and other andrenergic receptor agonists) optimally reduce the side effects associated with a CNS agent when a mechanoreceptor stimulator (i.e. guaifenesin (GUA)) is administered approximately 15 minutes after administration of the CNS agent and PSE; and (3) administration of GUA eliminates the need to use a very high dose of osmoactive polymers (or other osmoactive agents) which can complicate formulation preparation and disturb the subject's physiological osmotic balance.